Intellectual disability (ID) namely reduced intellectual functioning and limitations in daily-life skills such as personal care and communication, affects up to 2 % of the US population and poses an enormous burden on families, the healthcare system and society. This K99/R00 proposal is aimed at supporting the career development of Dr. M. Chiara Manzini as she explores the molecular mechanisms underlying ID, by studying the signaling gene CC2D1A, a known cause of ID in humans. The Mentored phase of the award is to be conducted at Children's Hospital Boston under the guidance of Dr. Christopher Walsh and the project is to be continued in Dr. Manzini's own laboratory after she secures an independent faculty position. Dr. Manzini's preliminary work firmly establishes loss of function mutations in CC2D1A as a cause of severe non-syndromic ID in humans and indicates that perturbations of Cc2d1a function in murine neurons lead to changes in neuronal morphology and in a reduction in dendritic spine number. Morphological and synaptic deficits in neurons are known correlates to behavioral defects of learning and memory and the initial part of this proposal (to be conducted during the mentored-phase of the award) will establish how loss of CC2D1A function may lead to cognitive impairment. Specific Aim 1 will investigate how the morphological defects observed following Cc2d1a knockdown affect the formation and function of synaptic contacts. Specific Aim 2 will explore the molecular mechanisms underlying the phenotypes observed upon Cc2d1a loss of function. Cc2d1a knockdown increases the transcriptional activity of NF-?B, an important regulator of dendrite outgrowth and synaptic plasticity and Specific Aim 2 will test whether and how NF-?B activity is involved in the morphological and functional phenotypes of Cc2d1a loss of function. Specific Aim 3 (to be completed in Dr. Manzini's lab) will further explore the biological role of Cc2d1a by also studying its mammalian paralog Cc2d1b. Our preliminary data from mass spectrometry analysis of Cc2d1a binding partners show that Cc2d1b is one of the most common proteins found in conjunction with Cc2d1a in the brain and we hypothesize that these proteins function in a complex and may have redundant roles. Thus, to understand the signaling activity of Cc2d1a and its involvement in the pathogenesis of ID, we need to study the interactions and the combined loss of function of both Cc2d1 family members. Dr. Manzini's long term career goal as an independent investigator is to outline the signaling pathways involved in the development of cognitive function and to continue studying genetic causes of ID, with the hope to identify additional signaling proteins involved in the etiology of the disease. This award will help her complete her training and provide a springboard to obtain data for a successful R01 application to fund her future work.